Development of rationale strategies for therapeutic intervention in aging processes is indispensable for preventing any age-related disorders including diabetes, heart attack, stroke, osteoporosis, cancer, chronic kidney disease, and dementia. Aging processes can be accelerated or suppressed by various environmental factors including nutrients in diet. Among various essential nutrients, recent studies have identified inorganic phosphate as an accelerator of aging processes. Mice defective in Klotho gene expression inappropriately retain inorganic phosphate in the body due to defects in renal phosphate excretion. Phosphate retention in Klotho deficient mice is associated with a premature aging syndrome, including shortened life span, hypogonadism, growth arrest, hearing loss, cognition impairment, osteopenia, vascular calcification, pulmonary emphysema, atrophy of the skin, muscle, and thymus. Importantly, these aging-like phenotypes are rescued by low phosphate diet. Thus, phosphate retention is toxic and accelerates aging. Klotho protein is secreted from kidney and functions as a soluble factor that promotes phosphate excretion into urine. These observations have raised the possibility that Klotho replacement therapy may prevent phosphate retention and suppress aging processes caused by Klotho deficiency. The long-term goal of this project is to prove this hypothesis. Klotho deficiency is typically observed in the aged and patients with chronic kidney disease (CKD). More than 26 million Americans, or 13% of total population, have CKD, which can result in renal failure and is increasingly recognized as a major public health problem in aging society. The goal of this project is to test whether Klotho replacement therapy is effective in the treatment of age-related disorders and CKD. Specific aims to attain this goal are 1) to determine whether administration of secreted Klotho protein restores accelerated aging in Klotho deficient mice and 2) to determine whether administration of secreted Klotho protein prevents progression of CKD in a mouse model. These experiments are expected to provide a rational therapeutic intervention in aging and CKD. PUBLIC HEALTH RELEVANCE: Project Narrative Reduced expression of an aging suppressor gene Klotho may be involved in the pathogenesis of aging and chronic kidney disease. The purpose of this project is to test whether supplementation of Klotho protein is effective in preventing progression of aging and chronic kidney disease in pre- clinical studies. If successful, this project would justify Klotho replacement therapy as a rational therapeutic intervention in aging and chronic kidney disease, which would have profound impacts on medical practice in general.